Hepatocellular cancer (HCC) is the most common solid organ tumor in the world. In the US, the incidence of HCC has nearly doubled over the past two decades. HCC is associated with an extremely poor prognosis because systemic therapies are largely nonspecific and ineffective. Attention has recently focused upon osteopontin (OPN) as a key mediator of HCC growth and metastasis. OPN is overexpressed in tumors, is the major phosphoprotein secreted by malignant cells in advanced metastatic cancer, is a key mediator of tumor cell migration and metastasis, and is a lead marker of HCC progression and metastasis. Both in vivo and in vitro gain- and loss-of-function experiments demonstrate a crucial functional role for OPN in local growth and metastasis of HCC. RNA aptamers are a unique class of therapeutic agents that carries several advantages over current therapies and as such, represent an exciting opportunity for molecularly targeted therapy. Aptamers are short ss RNA oligonucleotides that assume a stable three-dimensional shape to tightly and specifically bind selected protein targets to elicit a biological response. Aptamers possess binding affinities in the low nanomolar to picomolar range, are heat stable, lack immunogenicity, and possess minimal interbatch variability to effectively target extracellular targets. As a secreted phosphoprotein, OPN is an ideal therapeutic target for RNA aptamer mediated blockade of HCC growth and metastasis. We have isolated an RNA aptamer directed against human OPN (Kd ~18 nM). In this grant application, we propose to: 1) characterize the in vitro effect of our RNA aptamer on OPN-cell surface binding, signal transduction and adhesion/migration/invasion, 2) determine the in vivo efficacy of OPN-R3 for inhibition of local growth, metastasis and regression in a murine xenograft model of human HCC, and 3) determine the pharmacodynamic and toxicologic profile of the OPN aptamer to optimize in vivo dosing. It is our ultimate goal to translate this OPN aptamer into the clinical realm for HCC therapy. This grant utilizes RNA aptamers, a new therapeutic technology, to inhibit growth and spread of primary liver cancer, the most common solid organ tumor in the world.